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PubMed1978

Effects of the teratogenic folic acid antagonist, 9-methyl pteroylglutamic acid on uronic acid levels in fetal rat limbs.

Experimental pregnant rats were placed on a transitory folic acid-deficient regimen, i.e. dietary restriction of folic acid plus the teratogen and folic acid antagonist, 9-methyl pteroylglutamic acid; a regimen resulting in multiple congenital skeletal malformations. Controls received a folic acid-supplemented regimen. Accumulation of a primary component of the extracellular matrix, glycosaminoglycans (GAG), was quantitatively evaluated by measuring uronic acid concentrations in fetal limbs. On days 16 and 18 of gestation, fetal limbs were removed, pooled from each litter, and prepared for uronic acid, protein, and DNA quantitation. The treatment results in (1) a decreased rate of protein and DNA accumulation prior to day 16 of gestation, the rate not being affected from day 16 to day 18 of gestation; (2) a trend toward an increased rate of uronic acid accumulation prior to day 16 of gestation, and (3) a decreased rate of uronic acid accumulation from day 16 to day 18 of gestation. Furthermore, our observations confirm our earlier suggestion that there is a decreased rate of accumulation of some nonprotein component(s) in fetal limbs obtained from folic acid-deficient mothers from day 16 to day 18 of gestation.

Animals↗

PubMed1990

[Comparative bioavailability of eicosapentaenoic acid and docasahexaenoic acid from triglycerides, free fatty acids and ethyl esters in volunteers].

Comparative Bioavailability of Eicosapentaenoic Acid and Docosahexaenoic Acid from Triglycerides, Free Fatty Acids and Ethyl Esters in Volunteers. The bioavailability of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from triglycerides, free fatty acids and ethyl esters was investigated in 8 female volunteers in a randomized triple cross-over trial with baseline control. EPA/DHA was administered in capsules in form of triglycerides (1.68/0.72 g), free fatty acids (1.35/1.065 g) and ethyl esters (1.86/1.27 g). The resulting EPA/DHA plasma levels were determined and evaluated. The mean relative bioavailability of EPA/DHA compared to triglycerides was 186/136% from free fatty acids and 40/48% from ethyl esters. Maximal plasma levels were about 50% higher with free fatty acids and about 50% lower with ethyl esters as compared to triglycerides. The tolerability of the free fatty acids was much worse than that of triglycerides and ethyl esters. The main side effect was eructation.

Adult↗

PubMed1989

Biosynthesis of 18(RD)-hydroxyeicosatetraenoic acid from arachidonic acid by microsomes of monkey seminal vesicles. Some properties of a novel fatty acid omega 3-hydroxylase and omega 3-epoxygenase.

Microsomes of seminal vesicles of the cynomolgus monkey were incubated with [14C]5,8,11,14-eicosatetraenoic (arachidonic) acid and NADPH for 40 min at 37 degrees C and the products were characterized. Prostaglandins F2 alpha and E2 were the two main metabolites (approximately 52% of radioactivity), while 18(R)-hydroxy-cis-5,8,11,14-eicosatetraenoic acid (18(R)-HETE) was identified as the main, less polar product (approximately 13%). Significant biosynthesis of the 19-hydroxy or 20-hydroxy metabolites of arachidonic acid could not be detected. The formation of 18(R)-HETE was further investigated in the presence of a prostaglandin synthesis inhibitor, diclofenac sodium. The omega 3-hydroxylation was only partly supported by substituting NADH for NADPH. The hydroxyl oxygen of 18(R)-HETE was derived from the atmosphere and the omega 3-hydroxylation was inhibited by proadifen and partly inhibited by carbon monoxide. These findings suggest that 18(R)-HETE is formed by a cytochrome P-450 (P-450 omega 3). Linoleic acid and 8,11,14-eicosatetraenoic acid were also substrates of the enzyme, but stearic acid was not metabolized. 5,8,11,14,17-Eicosatetraenoic acid was oxygenated under these conditions mainly to 17,18-dihydroxy-5,8,11,14-eicosatetraenoic acid, presumably formed from 17(18)-epoxy-5,8,11,14-eicosatetraenoic acid by hydrolysis. The seminal microsomes thus seem to possess both omega 3-hydroxylase and omega 3-epoxygenase activity. These seminal vesicles also contain prostaglandin E 19-hydroxylase (Oliw, E.H., Kinn, A.-C., and Kvist, U. (1988) J. Biol. Chem. 263, 7222-7227). The presence of arachidonate omega 3-hydroxylase and prostaglandin E 19-hydroxylase was assessed in microsomes of adult and juvenile monkey livers. Arachidonic acid was metabolized extensively to diols (via epoxides), but 18-HETE could not be detected. In contrast, prostaglandin E1 was slowly hydroxylated mainly to 19-hydroxyprostaglandin E1 by both adult male and female juvenile hepatic microsomes. The results indicate that P-450 omega 3 of seminal vesicles might be a tissue-specific enzyme.

Animals↗

PubMed1983

Ascorbic acid, vitamin A, folic acid, and amino acids in blood of patients with hemophilia.

Blood levels of ascorbic acid, vitamin A, folic acid, and amino acids were studied in patients at the South Texas Comprehensive Hemophilia Center, San Antonio, TX. The mean plasma ascorbic acid level in hemophiliacs was significantly lower than controls (p less than 0.0001). This was observed despite a dietary ascorbic acid intake in excess of 66% of the Recommended Dietary Allowances (RDA). However, those subjects receiving specific factor replacement therapy at home and consuming at least 66% RDA of ascorbic acid maintained a mean plasma ascorbic acid level not significantly less than controls. Hemophilic subjects not on home therapy, on the other hand, had a mean plasma ascorbic acid level significantly below that of controls while receiving optimal dietary ascorbic acid. With prompt adequate medical care of bleeding episodes and with optimal nutrition, the demand for ascorbic acid needed for tissue repair in hemophilic patients may be lessened. Hemophiliacs had mean serum vitamin A, mean serum folate, and mean red cell folate levels that were not significantly different from controls. Significantly higher mean plasma arginine and lower, but not significantly lower, mean plasma ornithine levels were found in hemophilic subjects, suggesting altered arginase activity.

Adolescent↗

PubMed1996

Blood lipid docosahexaenoic and arachidonic acid in term gestation infants fed formulas with high docosahexaenoic acid, low eicosapentaenoic acid fish oil.

The effect of fish oil high in docosahexaenoic acid (22:6n-3) and low in eicosapentaenoic acid (20:5n-3) in formula on blood lipids and growth of full-term infants was studied. Infants were fed formula with about 15% oleic acid (18:1), 32% linoleic acid (18:2n-6), 4.9% linolenic acid (18:3n-3) and 0, 0.10, or 0.22% 22:6n-3, or 35% 18:1, 20% 18:2n-6, 2.1% 18:3n-3 and 0, 0.11, or 0.24% 22:6n-3 from 3 d to 16 wk of age (n = 16,18,17,21,17,16, respectively). The formulae had < 0.1% 20:5n-3 and no arachidonic acid (20:4n-6). Breast-fed infants (n = 26) were also studied. Plasma phospholipid and red blood cell (RBC) phosphatidylcholine (PC) and phosphatidylethanolamine (PE) fatty acids were determined at 3 d and 4, 8, and 16 wk of age. These longitudinal analyses showed differences in blood lipid 22:6n-3 between breast-fed and formula-fed infants depending on the feeding duration. At 16 wk, infants fed formula with 0.10, 0.11% 22:6n-3, or 0.22% 22:6n-3 had similar 22:6n-3 levels in the plasma phospholipid and RBC PC and PE compared with breast-fed infants, and higher 22:6n-3 than infants fed formula without 22:6n-3. Formula with 0.24% 22:6n-3, however, resulted in higher plasma phospholipid 22:6n-3 than in breast-fed infants at 16, but not 4 or 8 wk of age. Plasma and RBC phospholipid 20:4n-6 was lower in formula-fed than breast-fed infants, but no differences in growth were found. Higher blood lipid C20 and C22 n-6 and n-3 fatty acids in infants fed formula with 20% 18:2n-6 and 2.4% 18:3n-3 compared with 32% 18:2n-6 and 4.9% 18:3n-3 show the increase in blood lipid 22:6n-3 in response to dietary 22:6n-3 depending on other fatty acids in the formula.

Arachidonic Acid↗

PubMed1997

Fatty acid binding proteins reduce 15-lipoxygenase-induced oxygenation of linoleic acid and arachidonic acid.

Free fatty acids in plasma and cells are mainly bound to membranes and proteins such as albumin and fatty acid binding proteins (FABP), which can regulate their biological activities and metabolic transformations. We have investigated the effect of FABP and albumin on the peroxidation of linoleic acid (18:2) and arachidonic acid (20:4) by 15-lipoxygenase (15-LO). Rabbit reticulocyte 15-LO produced a rapid conversion of [1-14C]18:2 to 13-hydroxyoctadecadienoic acid (13-HODE) and [3H]20:4 to 15-hydroxyeicosatetraenoic acid (15-HETE). 13-HODE formation was reduced when intestinal FABP (I-FABP). liver FABP (L-FABP) or albumin was added. The relative ability of these proteins to reduce 15-LO induced formation of 13-HODE and 15-HETE was BSA > L-FABP > I-FABP. Smaller reductions in activity were observed with 20:4 as compared to 18:2. The IC50-values of I-FABP and L-FABP, using either 18:2 (3.4 microM) or 20:4 (3.4 microM), were 4.6 +/- 0.6 and 1.9 +/- 0.2 microM, respectively, for reduction of 13-HODE and 6.8 +/- 0.3 and 3.1 +/- 0.2 microM, respectively, for reduction of 15-HETE formation. The smaller 15-HETE reduction correlated with decreased binding of 20:4 to the FABP. Titration calorimetry also showed that the I-FABP IC50 for 18:2, 0.25 microM, was lower then for 20:4, 0.6 microM. Thus the reduction in fatty acid lipid peroxidation relates to the binding capacity of each FABP. We also demonstrated that 18:2 rapidly diffuses (flip-flops) across the phospholipid bilayer of small unilamellar vesicles (SUV) and measured partitioning of 18:2 between proteins and SUV by the pyranin fluorescence method [Kamp, F. and Hamilton, J.A. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 11367-11370]. Addition of proteins to SUV in buffer resulted in a complete desorption of 18:2 from SUV with a relative effect of BSA > L-FABP > I-FABP. This suggests that the relative effects of these proteins on 18:2 peroxidation will not be altered by the presence of membranes. Our results indicate that FAPBs protect intracellular polyunsaturated fatty acids against peroxidation and, through differential binding of 18:2 and 20:4, they may modulate the availability of these polyunsaturated fatty acids to intracellular oxidative pathways.

Animals↗

PubMed1999

Formation of 8,11,14-octadecatrienoic acid (18:3 n-4) from naturally occurring unique fatty acid, 9,12-hexadecadienoic acid (16:2 n-4), in animal cell cultures.

9,12-Hexadecadienoic acid (16:2 n-4), present in small amounts in fish oils as a naturally occurring unique fatty acid, was incorporated into the phospholipids in rat liver BRL-3A cells to a similar extent as linoleic acid (18:2 n-6). 11,14-Octadecadienoic acid (18:2 n-4) and 8,11,14-octadecatrienoic acid (18:3 n-4) were detected in the cellular lipids of BRL-3A cells when incubated in a medium supplemented with 16:2 n-4 methyl ester. The cellular levels of these acids increased in parallel with 16:2 n-4 methyl ester added to the medium. These compounds were probably formed through conversion from 16:2 n-4 to 16:3 n-4 by delta 6 desaturation, and then 18:3 n-4 was produced by elongation, and part of the surplus 16:2 n-4, not desaturated to 16:3 n-4, elongated to 18:2 n-4. These results suggested that 16:2 n-4 was desaturated by delta 6 desaturase in vitro. It was also shown that 16:2 n-4 inhibited arachidonic acid synthesis from exogenous linoleic acid in BRL-3A cells as efficiently as alpha-linolenic acid (18:3 n-3).

Animals↗

PubMed1984

Fertilization acid release in Urechis eggs. I. The nature of the acid and the dependence of acid release and egg activation on external pH.

The amount of fertilization acid produced by eggs of Urechis caupo , monitored by automatically back-titrating egg suspensions with base, depends linearly on the pH of the seawater. Above pH 7.0, at which no acid is released (Paul, M., Dev. Biol. 43, 299-312, 1975), acid release increased approximately 0.34 pmole/egg/0.1 pH unit. Activation (germinal vesicle breakdown) depended on the amount of acid release in natural seawater; it did not occur if eggs released less than 1.5 pmole acid/egg. When fertilization acid is released into HCO-3-free seawater and the pH permitted to decrease, the supernatant can be tested for the presence of a volatile acid, such as CO2, by bubbling with N2 and comparing the increase in pH as volatile acid is driven off with experiments in which HCl or CO2 is substituted for fertilization acid. An increase in pH of less than 0.2 pH units occurred on N2 bubbling when fertilization acid or HCl was used to acidify HCO-3-free seawater compared to an increase of greater than 0.5 pH units when CO2 was used. Therefore, most, if not all, of Urechis fertilization acid is not volatile, and since Paul (1975) showed that it is not a nonvolatile weak acid, it must be H+.

Animals↗

PubMed1984

Body protein metabolism and plasma amino acids in cirrhosis of the liver. The effect of varying the branched chain amino acid content of intravenous amino acid solutions.

Body protein metabolism and plasma amino acids were measured in 37 patients with stable cirrhosis of the liver to assess the effect of disease severity (Child's classification). Thirty two patients underwent a second series of measurements while nutrition was administered intravenously as one of five different infusions. Four infusions were formulations of amino acids with dextrose of varying branched chain amino acid content (100%, 53%, 35% and 16% branched chain to total amino acids). The fifth infusion was dextrose alone. No differences were detected in body protein synthesis and breakdown between patients on the basis of disease severity although some small differences were noted in the plasma amino acids. Infusion of dextrose alone and the 16% BCAA solution led to negative protein balance and a lowering of the plasma branched chain amino acid concentrations. Improved protein balance was observed with 35% BCAA, this solution also lowered the levels of methionine and aromatic amino acids. In those patients given 53% BCAA protein balance was achieved and the plasma branched chain amino acids elevated. Protein balance also occurred with 100% BCAA, in association with marked increases in underlying protein synthesis and breakdown and with this infusion there were marked elevations in the plasma branched chain amino acids and depression of the other plasma amino acids. The increase in protein breakdown with this last formulation was unexpected and may be harmful. On the basis of these findings it is suggested that the composition of the 53% and 35% solutions may be optimal to protein metabolism and manipulation of plasma amino acids in this group of patients.

Journal Article↗

PubMedDate not supplied

A residential study comparing the effects of diets rich in stearic acid, oleic acid, and linoleic acid on fasting blood lipids, hemostatic variables and platelets in young healthy men.

Dietary fat is known to influence the variables of blood coagulation and fibrinolysis associated with vascular disease. However, the role of fat content and/or fat composition of the diet in this regard is still not well understood. In the present study, we investigated the effects of three isoenergic diets of differing fat composition in nine healthy young men in a strictly controlled residential study. Subjects consumed the three experimental diets for periods of 2 weeks each, separated by a washout period of at least 5 weeks in a randomized crossover design. The diets provided 38% of total energy intake as fat, 45% as carbohydrate, and 17% as protein, and differed only with respect to the fatty acid composition (stearic acid-rich diet: 34.1% stearic acid, 36.6% oleic acid; oleic acid-rich diet: 65.8% oleic acid; linoleic acid-rich diet: 36.5% linoleic acid, 38% oleic acid). Blood samples were collected at the beginning and at the end of each dietary period from fasted subjects for determination of factor VII coagulant activity (FVIIc), activated factor VII (FVIIa), factor VII antigen (FVIIag), tissue plasminogen activator (tPA) activity, plasminogen activator inhibitor type 1 (PAI-1) activity, fibrinogen, prothrombin fragment 1+2 (F(1+2)), and plasma lipids. There were no significant differences between diets in fasting plasma concentrations of FVIIc, FVIIa, FVIIag, fibrinogen, F(1+2), PAI-1 activity, and tPA activity. Plasma concentrations of lipids (high density lipoproteins, low density lipoproteins, triacylglycerols, and total cholesterol) were also unaffected. Although there were no changes in platelet aggregation response and membrane fluidity observed in any of the diets, increased anti-aggregatory prostaglandin E(1) binding to platelet membranes was observed only in the case of linoleic acid-rich diet. In conclusion, diets with very different fatty acid compositions, at 38% of energy as fat intake, did not significantly influence blood coagulation, fibrinolysis, or blood lipids in the fasting state in young healthy men.

Journal Article↗

PubMed2000

Biological modification of the fatty acid group in an emulsan by supplementing fatty acids under conditions inhibiting fatty acid biosynthesis.

When the concentration of the antibiotic cerulenin was increased up to 3.0 mg/l in medium containing ethanol as a carbon source, the specific growth rate of Acinetobacter calcoaceticus and the fatty acid content of the emulsan decreased from 0.179 h(-1) and 13.9% to 0.015 h(-1) and 3.4%, respectively. The emulsifying activity in medium containing cerulenin decreased with increasing cerulenin concentration. In the culture containing 3.0 mg/l cerulenin, fatty acid biosynthesis was inhibited. Various fatty acids were added to this inhibitory culture as a second carbon source to modify the fatty acid group in the emulsan. When an odd-numbered fatty acid was added, the resulting emulsan was found to have other odd-numbered fatty acids that were not present originally. Among the emulsan produced from even-numbered fatty acids, the emulsan produced from myristic acid (C14) contained the greatest amount of the same-numbered fatty acids. When the amount of supplemental myristic acid was increased, the myristic acid content in the emulsan increased, but its emulsifying activity decreased.

Journal Article↗

PubMed1996

Peroxygenase-Catalyzed Fatty Acid Epoxidation in Cereal Seeds (Sequential Oxidation of Linoleic Acid into 9(S),12(S),13(S)-Trihydroxy-10(E)-Octadecenoic Acid).

Peroxygenase-catalyzed epoxidation of oleic acid in preparations of cereal seeds was investigated. The 105,000g particle fraction of oat (Avena sativa) seed homogenate showed high peroxygenase activity, i.e. 3034 [plus or minus] 288 and 2441 [plus or minus] 168 nmol (10 min)-1 mg-1 protein in two cultivars, whereas the corresponding fraction obtained from barley (Hordeum vulgare and Hordeum distichum), rye (Secale cereale), and wheat (Triticum aestivum) showed only weak activity, i.e. 13 to 138 nmol (10 min)-1 mg-1 protein. In subcellular fractions of oat seed homogenate, peroxygenase specific activity was highest in the 105,000g particle fraction, whereas lipoxygenase activity was more evenly distributed and highest in the 105,000g supernatant fraction. Incubation of [1-14C]linoleic acid with the 105,000g supernatant of oat seed homogenate led to the formation of several metabolites, i.e. in order of decreasing abundance, 9(S)-hydroxy-10(E),12(Z)-octadecadienoic acid, 9(S),12(S),13(S)-trihydroxy-10(E)-octadecenoic acid, cis-9,10-epoxy-12(Z)-octadecenoic acid [mainly the 9(R),10(S) enantiomer], cis-12,13-epoxy-9(Z)-octadecenoic acid [mainly the 12(R),13(S) enantiomer], threo-12,13-dihydroxy-9(Z)-octadecenoic acid, and 12(R),13(S)-epoxy-9(S)-hydroxy-10(E)-octadecenoic acid. Incubation of linoleic acid with the 105,000g particle fraction gave a similar, but not identical, pattern of metabolites. Conversion of linoleic acid into 9(S),12(S),13(S)-trihydroxy-10(E)-octadecenoic acid, a naturally occurring oxylipin with antifungal properties, took place by a pathway involving sequential catalysis by lipoxygenase, peroxygenase, and epoxide hydrolase.

Journal Article↗

PubMed1989

Entropy as a factor in the binding of gamma-aminobutyric acid and nipecotic acid to the gamma-aminobutyric acid transport system.

Nipecotic acid is one of the most potent competitive inhibitors and alternative substrates for the high-affinity gamma-aminobutyric acid transport system in neurons, but the structural basis of this potency is unclear. Because gamma-aminobutyrate is a highly flexible molecule in solution, it would be expected to lose rotational entropy upon binding to the transport system, a change which does not favor binding. Nipecotic acid, in contrast, is a much less flexible molecule, and one would expect the loss of conformational entropy upon binding to be smaller thus favoring the binding of nipecotic acid over gamma-aminobutyric acid. To investigate this possibility, the thermodynamic parameters, delta G degrees, delta H degrees, and delta S degrees, were determined for the binding of gamma-aminobutyrate and nipecotic acid to the high affinity GABA transport system in synaptosomes. In keeping with expectations, the apparent entropy change for nipecotic acid binding (112 +/- 13 J.K-1) was more favorable than the apparent entropy change for gamma-aminobutyric acid binding (61.3 +/- 6.6 J.K-1). The results suggest that restricted conformation per se is an important contributory factor to the affinity of nipecotic acid for the high-affinity transport system for gamma-aminobutyric acid.

Animals↗

PubMed1987

Induction of cytosolic and microsomal epoxide hydrolases and proliferation of peroxisomes and mitochondria in mouse liver after dietary exposure to p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid.

The effects of dietary exposure to 0.125% (w/w) p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid or 2,4,5-trichlorophenoxyacetic acid on the content of peroxisomes and levels of certain xenobiotic-metabolizing enzymes in mouse liver have been investigated. In agreement with the literature on rat liver 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid were found to cause extensive proliferation of peroxisomes (as judged by the total levels of "mitochondrial" protein, carnitine acetyltransferase, cyanide-insensitive palmitoyl-CoA oxidation and catalase) in mouse liver. On the other hand, exposure to p-chlorophenoxyacetic acid did not significantly affect any of these parameters. As with certain other peroxisome proliferators, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid increased total cytochrome oxidase activity as well. In addition, dietary exposure to 2,4-dichlorophenoxyacetic acid and to 2,4,5-trichlorophenoxyacetic acid resulted in increases in the activities of cytosolic and microsomal epoxide hydrolases in mouse liver and generally less pronounced increases in the total cytosolic glutathione transferase activity and microsomal content of cytochrome P-450. In the case of cytochrome P-450, this process can be said to be a true induction (i.e. the amount of enzyme protein is increased), because the assay procedure for cytochrome P-450 measures holoenzyme amount. Immunoquantitation demonstrated that this was also the case for the changes in cytosolic epoxide hydrolase. The dramatic differences in proliferation of peroxisomes and induction of xenobiotic-metabolizing enzymes seen here with compounds differing relatively little in structure may indicate that a receptor mechanism of some kind is involved.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed2001

Biosynthesis of sialylated lipooligosaccharides in Haemophilus ducreyi is dependent on exogenous sialic acid and not mannosamine. Incorporation studies using N-acylmannosamine analogues, N-glycolylneuraminic acid, and 13C-labeled N-acetylneuraminic acid.

Haemophilus ducreyi is a Gram-negative bacterium that causes chancroid, a sexually transmitted disease. Cell surface lipooligosaccharides (LOS) of H. ducreyi are thought to play important biological roles in host infection. The vast majority of H. ducreyi strains contain high levels of sialic acid (N-acetylneuraminic acid, NeuAc) in their LOS. Here we investigate the biosynthetic origin of H. ducreyi sialosides by metabolic incorporation studies using a panel of N-acylmannosamine and sialic acid analogues. Incorporation of sialosides into LOS was assessed by matrix-assisted laser desorption and electrospray ionization mass spectrometry. A Fourier transform ion cyclotron resonance mass spectrometer provided accurate mass measurements, and a quadrupole time-of-flight instrument was used to obtain characteristic fragment ions and partial carbohydrate sequences. Exogenously supplied N-acetylmannosamine analogues were not converted to LOS-associated sialosides at a detectable level. In contrast, exogenous (13)C-labeled N-acetylneuraminic acid ([(13)C]NeuAc) and N-glycolylneuraminic acid (NeuGc) were efficiently incorporated into LOS in a dose-dependent fashion. Moreover, approximately 1.3 microM total exogenous sialic acid was sufficient to obtain about 50% of the maximum production of sialic acid-containing glycoforms observed under in vitro growth conditions. Together, these data suggest that the expressed levels of sialylated LOS glycoforms observed in H. ducreyi are in large part controlled by the exogenous concentrations of sialic acid and at levels one might expect in vivo. Moreover, these studies show that to properly exploit the sialic acid biosynthetic pathway for metabolic oligosaccharide engineering in H. ducreyi and possibly other prokaryotes that share similar pathways, precursors based on sialic acid and not mannosamine must be used.

Biological Transport↗

PubMed1991

Novel class of amino acid antagonists at non-N-methyl-D-aspartic acid excitatory amino acid receptors. Synthesis, in vitro and in vivo pharmacology, and neuroprotection.

The isoxazole amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) (1), which is a highly selective agonist at the AMPA subtype of excitatory amino acid (EAA) receptors, has been used as a lead for the development of two novel EAA receptor antagonists. One of the compounds, 2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionic acid (AMOA, 7), was synthesized via O-alkylation by ethyl chloroacetate of the amino acid protected AMPA derivative 4. The other compound, 2-amino-3-[2-(3-hydroxy-5-methylisoxazol-4-yl)-methyl-5-methyl-3-+ ++oxoisoxazolin -4-yl]propionic acid (AMNH, 14) was synthesized with use of 4-(chloromethyl)-3-methoxy-5-methylisoxazole (8) as the starting material. The intermediate 4-(chloromethyl)-2-(3-methoxy-5-methylisoxazol-4-yl)methyl-5-me thylisoxazolin- 3-one (11) was converted into the acetamidomalonate (12), which was stepwise deprotected to give 14. Compounds 7 and 14 were stable in aqueous solution at pH values close to physiological pH. Neither 7 nor 14 showed detectable affinities for the receptor, ion channel, or modulatory sites of the N-methyl-D-aspartic acid (NMDA) receptor complex. Quantitative receptor autoradiographic and conventional binding techniques were used to study the affinities of 7 and 14 for non-NMDA receptor sites. Both compounds were inhibitors of the binding of [3H]AMPA (IC50 = 90 and 29 microM, respectively). Compounds 14 and 7 were both very weak inhibitors of the high-affinity binding of radioactive kainic acid [( 3H]KAIN). Compound 14, but not 7, was, however, shown to be an inhibitor of low-affinity [3H]KAIN binding (IC50 = 40 microM) as determined in the presence of 100 mM calcium chloride. In the rat cortical slice preparation, 7 was shown to antagonize excitation induced by 1 with some selectivity, whereas 14 proved to be a rather selective antagonist of KAIN-induced excitation. Both antagonists showed very weak effects on the excitatory effects of NMDA. Compound 7 was a poor antagonist of excitation by quisqualic acid (2), whereas 14 did not affect excitation by this nonselective AMPA receptor agonist. On cat spinal neurones, both 7 and 14 reduced excitations by 1 and KAIN, but, again, the excitatory effects of 2 were much less sensitive. Compound 14 and, in particular, 7 effectively protected rat striatal neurones against the neurotoxic effects of KAIN, whereas the toxic effects of 1 were reduced only by 7. Neither antagonist showed protection against the cell damage caused by intrastriatal injection of the NMDA agonist quinolinic acid.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1968

Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycaemic fatty acids. Oxidative phosphorylation and mitochondrial oxidation of pyruvate, 3-hydroxybutyrate and tricarboxylic acid-cycle intermediates.

1. The effects of the hypoglycaemic compound pent-4-enoic acid, and of four structurally related non-hypoglycaemic compounds (pent-2-enoic acid, pentanoic acid, cyclopropanecarboxylic acid and cyclobutanecarboxylic acid), on several reactions in rat liver mitochondria were determined. 2. The use of manometric techniques for measurements of oxidations and of phosphorylation is critically discussed. 3. Pent-4-enoic acid and pentanoic acid uncoupled oxidative phosphorylation at low concentrations, but usually by not more than about 50%. 4. All the compounds, except cyclobutanecarboxylic acid, strongly inhibited the oxidation of pyruvate and 2-oxoglutarate, but the oxidations of succinate, citrate and 3-hydroxybutyrate were not strongly inhibited. 5. All the compounds, except cyclobutanecarboxylic acid, inhibited decarboxylation of [1-(14)C]pyruvate with ferricyanide as electron acceptor. 6. All the compounds, except pent-2-enoic acid, caused mitochondrial swelling after a time-lag.

Animals↗

PubMed1976

Microbiological degradation of bile acids. The conjugation of a certain cholic acid metabolite with amino acids in Corynebacterium equi.

1. (4R)-4[4alpha-(2-Carboxyethyl)-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-1beta-yl]valeric acid (II) could not be utilized by Arthrobacter simplex, even though the acid was one of the metabolites formed from cholic acid (I) by this organism. Therefore the further degradation of the acid (II) by Corynebacterium equi was investigated to identify the intermediates involved in the cholic acid degradation. 2. The organism, cultured in a medium containing the acid (II) as the sole source of carbon, produced unexpected metabolites, the conjugates of this original acid (II) with amino acids or their derivatives, although the yield was very low. These new metabolites were isolated and identified by chemical synthesis as the Na-((4R)-4-[4alpha-(2-carboxyethyl)-3a alpha-hexahydro-7a beta-methyl-5-oxoindan-1 beta-yl]-valeryl) derivatives of L-alanine, glutamic acid, O-acetylhomoserine and glutamine, i.e. compounds (IIIa), (IIIb), (IIId) respectively. 3. The possibility that the bacterial synthetic reaction observed in the acid (II) metabolism with C. equi is analogous to peptide conjugation known in both animals and higher plants is discussed. A possible mechanism for this bacterial conjugation is also considered.

Alanine↗